Obesity, primarily a consequence of poor dietary choices and an increased sedentary lifestyle, has become a global pandemic that brings with it enormous medical, social, and economic challenges. Not only does obesity increase the risk of cardiovascular disease and certain cancers, but it is also recognized as a key driver of other metabolic syndrome (MetS) components. These components include insulin resistance, hyperglycemia with prediabetes or type 2 diabetes, dyslipidemia, and hypertension, and are underlying contributors to systemic metabolic dysfunction. More recently, obesity and diet-induced metabolic dysfunction have been identified as risk factors for the development of a wide variety of neurological disorders in both the central and peripheral nervous systems. An abundance of literature has shown that obesity is associated with mild cognitive impairment and altered hippocampal structure and function, and there is a robust correlation between obesity and Alzheimer’s type dementia. Similarly, many reports show that both the autonomic and somatic components of the peripheral nervous system are impacted by obesity. The autonomic nervous system, under control of the hypothalamus, displays altered catabolic and anabolic processes in obese individuals attributed to sympathetic-parasympathetic imbalances. A close association also exists between obesity and polyneuropathy, a complication most commonly found in prediabetic and diabetic patients, and is likely secondary to a combination of obesity-induced dyslipidemia with hyperglycemia. This review will outline the pathophysiological development of obesity and dyslipidemia, discuss the adverse impact of these conditions on the nervous system, and provide evidence for lipotoxicity and metabolic inflammation as the drivers underlying the neurological consequences of obesity. In addition, this review will examine the benefits of lifestyle and surgical interventions in obesity-induced neurological disorders.

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share key features, including accumulation of the RNA-binding protein TDP-43. TDP-43 regulates RNA homeostasis, but it remains unclear whether RNA stability is affected in these disorders. We use Bru-seq and BruChase-seq to assess genome-wide RNA stability in ALS patient-derived cells, demonstrating profound destabilization of ribosomal and mitochondrial transcripts. This pattern is recapitulated by TDP-43 overexpression, suggesting a primary role for TDP-43 in RNA destabilization, and in postmortem samples from ALS and FTD patients. Proteomics and functional studies illustrate corresponding reductions in mitochondrial components and compensatory increases in protein synthesis. Collectively, these observations suggest that TDP-43 deposition leads to targeted RNA instability in ALS and FTD, and may ultimately cause cell death by disrupting energy production and protein synthesis pathways.

Emerging data establish dyslipidemia as a significant contributor to the development of diabetic neuropathy. In this review we discuss how separate metabolic imbalances, including hyperglycemia and hyperlipidemia, converge on mechanisms leading to oxidative stress in dorsal root ganglia sensory neurons. We conclude with suggestions for novel therapeutic strategies to prevent or reverse diabetes-induced nerve degeneration.

Patients with metabolic syndrome, which is defined as obesity, dyslipidemia, hypertension and impaired glucose tolerance (IGT), can develop the same macro- and microvascular complications as patients with type 2 diabetes, including peripheral neuropathy. In type 2 diabetes, glycemic control has little effect on the development and progression of peripheral neuropathy, suggesting that other metabolic syndrome components may contribute to the presence of neuropathy. A parallel phenomenon is observed in patients with prediabetes and metabolic syndrome, where improvement in weight and dyslipidemia more closely correlates with restoration of nerve function than improvement in glycemic status. The goal of the current study was to develop a murine model that resembles the human condition. We examined longitudinal parameters of metabolic syndrome and neuropathy development in six mouse strains/genotypes (BKS-wt, BKS-Leprdb/+, B6-wt, B6-Leprdb/+, BTBR-wt, and BTBR-Lepob/+) fed a 54% high-fat diet (HFD; from lard). All mice fed a HFD developed large-fiber neuropathy and IGT. Changes appeared early and consistently in B6-wt mice, and paralleled the onset of neuropathy. At 36 weeks, B6-wt mice displayed all components of the metabolic syndrome, including obesity, IGT, hyperinsulinemia, dyslipidemia and oxidized low density lipoproteins (oxLDLs). Dietary reversal, whereby B6-wt mice fed a HFD from 4-20 weeks of age were switched to standard chow for 4 weeks, completely normalized neuropathy, promoted weight loss, improved insulin sensitivity, and restored LDL cholesterol and oxLDL by 50% compared with levels in HFD control mice. This dietary reversal model provides the basis for mechanistic studies investigating peripheral nerve damage in the setting of metabolic syndrome, and ultimately the development of mechanism-based therapies for neuropathy.